CA1125756A - Indane-acetic acid aminoesters, their preparation and their use in therapy - Google Patents
Indane-acetic acid aminoesters, their preparation and their use in therapyInfo
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- CA1125756A CA1125756A CA331,498A CA331498A CA1125756A CA 1125756 A CA1125756 A CA 1125756A CA 331498 A CA331498 A CA 331498A CA 1125756 A CA1125756 A CA 1125756A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
"NEW INDANE-ACETIC ACID AMINOESTERS, THEIR PREPARATION
AND THEIR USE IN THERAPY".
The compounds of the formula:
(I) in which R represents an ethyl or isopropyl group, which, like their ammonium salts and addition salts with acids, have analgesic properties, are prepared from the compounds:
or
"NEW INDANE-ACETIC ACID AMINOESTERS, THEIR PREPARATION
AND THEIR USE IN THERAPY".
The compounds of the formula:
(I) in which R represents an ethyl or isopropyl group, which, like their ammonium salts and addition salts with acids, have analgesic properties, are prepared from the compounds:
or
Description
~ ~ 5 75 ~
Process for the preparation of new indane-acetic acid aminoesters which are useful in therapy The present invention relates to the preparation of new indane aminoesters which are useful in thera~y, The said compounds correspond to the general formula:
R--~3/ ~ COOC~12C~I~r~\N Q
~) in which R is an ethyl or isopropyl group.
me invention also relates to the preparation of addition saits of the compounds of the formula I, namely addition salts with acids or quaternary ammonium salts.
The addition salts with acids are obtained by reac-tion with an inorganic or organic acid in accordance with a method which is in itself known.
Amongst the acids which can be used for this purpose, there may be mentioned, in particular, hydrochloric, sul-phuric, phosphoric, oxalic, succinic, methanesulphonic, cyclohexylsulphamic, formic, aspartic, glutamic, N-acetyl-aspartic, N-acetylglutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic and p-toluenesulphonic acids.
The compounds prepared according to the invention possess valuable pharmacological actions and can be useful in therapy as analgesic agents.
m erapeutic compositions are thus obtained ~hich are usefulJ in particular, for the trea~tment of pain an~ are i~
~'25756 characterised in that they con-Lain, in association with a physioloyically acceptable excipient, an effective amount of at least one compound oE the formula (I) or one of its non-toxic addition salts.
The compounds of formula (I) can be made by linking a moiety containing the indane portion to a moiety containing the phenylpiperazine portion, while eliminating a halogen atom attached to one or other portion. Thus the process of the present invention, broadly construed, for making the compounds of formula (I) comprises reacting a derivative of the acid of the formula (II):
,C~I3 / ~ (II) which derivative is a metal salt or an acyl halide or a haloethyl ester, with a piperazine of formula (VI):
ZN N ~ ~ (VI) wherein Z is YCH2CH2- (Y being a halogen atom) when the derivative is a metal salt Z is HOCH2CH2 when the derivative is an acyl halide and Z is H when the derivative is a haloethyl ester.
When the salt is desired, the cornpound of Xormula (I) is converted by standard methods to one of its addition salts with an acid or to i-ts quaternary ammonium salt.
Accordingly, several d:istinct methods of making the compounds of formula (I) are each an embodiment of the invention, as follows:
a) the halides (III) of the acids of the formula (II):
,CH3 ~ \ / \ ~ \ (II) in which R has the same meaning as above, are reacted with the aminoalcohol of the formula:
~CH2c~2N N - ~ or b) the inorganic salts (IV) of the acids of the formula (II) are reacted with a hallde of the formula:
Process for the preparation of new indane-acetic acid aminoesters which are useful in therapy The present invention relates to the preparation of new indane aminoesters which are useful in thera~y, The said compounds correspond to the general formula:
R--~3/ ~ COOC~12C~I~r~\N Q
~) in which R is an ethyl or isopropyl group.
me invention also relates to the preparation of addition saits of the compounds of the formula I, namely addition salts with acids or quaternary ammonium salts.
The addition salts with acids are obtained by reac-tion with an inorganic or organic acid in accordance with a method which is in itself known.
Amongst the acids which can be used for this purpose, there may be mentioned, in particular, hydrochloric, sul-phuric, phosphoric, oxalic, succinic, methanesulphonic, cyclohexylsulphamic, formic, aspartic, glutamic, N-acetyl-aspartic, N-acetylglutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic and p-toluenesulphonic acids.
The compounds prepared according to the invention possess valuable pharmacological actions and can be useful in therapy as analgesic agents.
m erapeutic compositions are thus obtained ~hich are usefulJ in particular, for the trea~tment of pain an~ are i~
~'25756 characterised in that they con-Lain, in association with a physioloyically acceptable excipient, an effective amount of at least one compound oE the formula (I) or one of its non-toxic addition salts.
The compounds of formula (I) can be made by linking a moiety containing the indane portion to a moiety containing the phenylpiperazine portion, while eliminating a halogen atom attached to one or other portion. Thus the process of the present invention, broadly construed, for making the compounds of formula (I) comprises reacting a derivative of the acid of the formula (II):
,C~I3 / ~ (II) which derivative is a metal salt or an acyl halide or a haloethyl ester, with a piperazine of formula (VI):
ZN N ~ ~ (VI) wherein Z is YCH2CH2- (Y being a halogen atom) when the derivative is a metal salt Z is HOCH2CH2 when the derivative is an acyl halide and Z is H when the derivative is a haloethyl ester.
When the salt is desired, the cornpound of Xormula (I) is converted by standard methods to one of its addition salts with an acid or to i-ts quaternary ammonium salt.
Accordingly, several d:istinct methods of making the compounds of formula (I) are each an embodiment of the invention, as follows:
a) the halides (III) of the acids of the formula (II):
,CH3 ~ \ / \ ~ \ (II) in which R has the same meaning as above, are reacted with the aminoalcohol of the formula:
~CH2c~2N N - ~ or b) the inorganic salts (IV) of the acids of the formula (II) are reacted with a hallde of the formula:
2 ~ ~
in which Y is a halogen atom.
The steps of the process according to the invention are illustrated in the following scheme:
. - ~, .. ... . .
Cj~) 0C~12C~124~3 / ~COO~ C ~ 2 2 ¦~3 / t YC1~2C~12~\1`; ~;~
- (X -- halogen atom) (M = metal) ~c) In order to prepare the compounds of the formula I, it is also possible to use the method illustrated by -the following scheme:
~ ~ ~ 3 R 0~ 2 ~ R 0~ 2 2 ~ill) (V) iii~' N ~ R~ COOcil2C~
+(v3 _ 5 - ~1~575~
in which: R is an ethyl or isopropyl group and X and 'f are halogen atoms.
a) The acid halides of the formula III are reacted with a halogenoalcohol HOCH2CH2Y in an organic solvent, suoh as acetone, chloroform, methylene chloride or an aroma-tic hydrocarbon, in the presence or absence of a base such as pyridine or triethylamine~ and b) the resulting halogenoester of the formula V is reacted with m-trifluorome-thylphenylpiperazine:
~ N
/ ~
in an organic solvent, such as acetone, chloroform, methy-lene chloride or an aromatic hydrocarbon, using either twice the amour~t of rn--trifluoromethylphenylpiperazine or a tertiary nitrogen-containing base such as triethylamine.
The halide of the formula (V) is new.
m e invention is illustrated below by non-limiting synthesis examples:
Example 1 2-Methvl-(2-ethylindan-5-yl~-acetic acid chloride.
A solution of 57 g of 2-methyl-(2-ethylindan-5-yl~-acetic acid and 40 ml of thionyl chloride in 200 ml of ben-zene is heated under reflux for 2 hours. The solvent and the excess thionyl chloride are then evaporated off in vacuo.
m e resulting oil is then distilled in vacuo. 56 g of - 6 ~ llZ575~
2-methyl-(2-e-thylindan-5-yl)-ace~tic acid chloride are thus recovered in the form of a liquid:
Boiling point (l mm Hg) = 125 - 128C.
Example 2 2-Meth~1-(2-ethylindan-5-yl)-acetic acid (m-trifluorornethyl-phenyl~-piperazinoethyl ester hydrochloride 6~ ml of triethylamine are added dropwise to 64 g of (m-trifluoromethylphenyl)-piperazinoethanol hydrochloride in 600 m~ of anhydrous benzene.
lo After the addition is complete, the mixture is stir-red for 30 minutes at ambient temperature and 55.9 g of the 2-methyl-(2-ethylindan-5-yl)-acetic acid chloride pre-pared in Example 1, in 100 ml of benzene, are then added dropwise.
After the addition is complete, the reaction mixture is heated under reflux for 5 hours.
After cooling, the organic phase is washed carefully with water, with a 5 % strength soiution of sodium hydroxide in the presence of icé, and then again with water, and dried over sodit~n carbonate. After evaporating off the benzene, the residue, which is in the form of a-liquid, is dissolved in acetone, and a solution of hydrogen chloride in ~her is added until the pH is acid. The crystals formed are fil-tered off and washed carefully with acetone. 70 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid (m-trifluoromethyl-phenyl)-piperazinoethyl estér hydrochlorlde are thus isolated in the form of white crystals having a melting point of 199-~01c Example 3 2-Methyl-(~-lsoproPylindan-5-yl)-acetic acld chloride.
By following the procedure of Example l, but using 31 g of 2-rnethyl-(2-isopropylindan-5-yl)-acetic acid, 30 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid chloride are recovered in the form of a liquid:
Boiling point (1 mm Hg) = 150C.
Example 4 2-Methyl-(2-iso~y~lindan-5-y~l~-acetic acid (m-trifluoro-meth~lphenyl)-Piperazinoethyl ester.
A solution of 6.9 g of the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid chloride prepared in Example 3, in 2Q ml of benzene, is added dropwise to a solution of 7.5 g of (m-trifluoromethylphenyl)-piperazinoethanol and 4.5 ml of triethylamine in 100 ml of benzene.
After the addition is complete, the reaction mixture is heated under reflux for 5 hours.
After cooling, the organic phase is washed carefully with water and dried over sodium carbonate and the benzene is evaporated off in vacuo. I~e resulting residue is taken up in cold pentane. The crystals formed are fil-tered off and washed with pentane. 11 g of 2-methyl-~2-isopropylindan-5-yl~-acetic acid (m-trifluoromethylphenyl)-piperazinoethyl ester are thus isolated in the form of white crystals having a melting point of 56 - 58C.
.
llZS75~
Example ~
2-Methyl-~2-ethylindan-5-~1)-acetic acid ~m-trifluoromethyl-phenyl)-P~ipera-zinoethyl-ester hvdrochloride 21.8 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid are treated with a solution of sodium methylate, prepared from 2.3 g of sodium dissolved in 40 ml of methanol.
After evaporating off the solvent, the sodium salt of the acid is obtained in the form of a white powder.
A solution of this sodium salt and 29.3 g of ~-[~m-trifluoromethylphenyl)-piperazino]-chloroethane in 100 ml of xylene is hea-ted under reflux for 7 hours.
After cooling the reaction mixture, the organic phase is washed with water and dried over sodium carbonate.
After evaporating off the solvent, the base is isolated in the fQrm of a liquid.
This base is taken up in acetone, and a solution of hydrogen chloride in ether is added until the pH is acid.
The resulting crystals are washed carefully with acetone and dried. 36 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid (m~trifluoromethylphenyl)-piperazinoethyl ester hydro-chloride are thus recovered in the form of white crystals having a melting point of` 200 ~ 2C.
Example 6 2-Methyl-~2-isopro y ~ m-tr fluoro-methvlphenyl~-piperazinoe-thyl _ster.
By following the procedure of Example 5, but using 23.2 g OI 2-methyl-(2-isopropylindan-~-yl~-acetic acid, 11~575fj 37 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid (m--tri-fluoromethylphenyl)-piperazinoethyl ester, as the base, are recovered in the form of white crystals having a me:Lting pOi~lt of 56 - 58C.
Example 7 2-Methyl-(2-e~thylindan-5-yl)-acetic acid bromoet~yl ester.
Formula V R = ethyl Y = Br Method A:
A solution of 4.4 g of 2-me-thyl-(2 ethylindan-5-yl)-acetic acid chloride and 2.45 g of 2-bromoethanol in 50 ml of anhydrous acetone is heated under reflux for 4 hours.
After evaporating off the solven-t, the resul-ting oily residue is dissolved in ether and the ether solution is washed, in the presence of ice, with an aqueous solution of sodium bicarbonate and with water and is then dried over sodium sulphate. After filtering and evaporating off the solvent, 5.9 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid bromoethyl ester are obtained in the form of an oily residue which is used in the crude state for thef~lowingstep.
Method B:
-A solution of 12 g of 2-methyl-(2-e-thylindan-5-yl)-acetic acid chloride in 15 ml of chloroform is added, at 0~C, to a solution of 6.4 g of 2-bromoethanol and 5.5 ml of pyridine in 30 ml of chloroform.
After the addition is complete, the reaction mixture is heated under reflux for 1 hour.
` After cooling9 the reaction mix-ture is washed with 11~575~
wa-ter, with 5 % strength hydrochloric acid and then again with water. The chloroforrn phase is dried and, after evaporating off the solven~t, the oily residue is distilled in vacuo. 13.7 g of 2~methy]-(2-e-thylindan-5-yl)-acetic acid bromoethyl ester are thus recovered in the form of an oil.
Boiling poin-t ~0.2 mm Hg) = 138-lL~C.
Example 8 2-Methy]-(2-ethyl _dan-~-yl)-acetic acid m-trifluoromethyl-phcnylpi~erazinoethyl ester hydrochloride.
~ formula I R = ethyl Method A:
A solution of 5.9 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid brornoethyl ester obtained by method ~ of Example 7, in 15 ml of anhydrous acetone, is added to a solution of 4.2 g of m-trifluoromethylphenylpiperazine and
in which Y is a halogen atom.
The steps of the process according to the invention are illustrated in the following scheme:
. - ~, .. ... . .
Cj~) 0C~12C~124~3 / ~COO~ C ~ 2 2 ¦~3 / t YC1~2C~12~\1`; ~;~
- (X -- halogen atom) (M = metal) ~c) In order to prepare the compounds of the formula I, it is also possible to use the method illustrated by -the following scheme:
~ ~ ~ 3 R 0~ 2 ~ R 0~ 2 2 ~ill) (V) iii~' N ~ R~ COOcil2C~
+(v3 _ 5 - ~1~575~
in which: R is an ethyl or isopropyl group and X and 'f are halogen atoms.
a) The acid halides of the formula III are reacted with a halogenoalcohol HOCH2CH2Y in an organic solvent, suoh as acetone, chloroform, methylene chloride or an aroma-tic hydrocarbon, in the presence or absence of a base such as pyridine or triethylamine~ and b) the resulting halogenoester of the formula V is reacted with m-trifluorome-thylphenylpiperazine:
~ N
/ ~
in an organic solvent, such as acetone, chloroform, methy-lene chloride or an aromatic hydrocarbon, using either twice the amour~t of rn--trifluoromethylphenylpiperazine or a tertiary nitrogen-containing base such as triethylamine.
The halide of the formula (V) is new.
m e invention is illustrated below by non-limiting synthesis examples:
Example 1 2-Methvl-(2-ethylindan-5-yl~-acetic acid chloride.
A solution of 57 g of 2-methyl-(2-ethylindan-5-yl~-acetic acid and 40 ml of thionyl chloride in 200 ml of ben-zene is heated under reflux for 2 hours. The solvent and the excess thionyl chloride are then evaporated off in vacuo.
m e resulting oil is then distilled in vacuo. 56 g of - 6 ~ llZ575~
2-methyl-(2-e-thylindan-5-yl)-ace~tic acid chloride are thus recovered in the form of a liquid:
Boiling point (l mm Hg) = 125 - 128C.
Example 2 2-Meth~1-(2-ethylindan-5-yl)-acetic acid (m-trifluorornethyl-phenyl~-piperazinoethyl ester hydrochloride 6~ ml of triethylamine are added dropwise to 64 g of (m-trifluoromethylphenyl)-piperazinoethanol hydrochloride in 600 m~ of anhydrous benzene.
lo After the addition is complete, the mixture is stir-red for 30 minutes at ambient temperature and 55.9 g of the 2-methyl-(2-ethylindan-5-yl)-acetic acid chloride pre-pared in Example 1, in 100 ml of benzene, are then added dropwise.
After the addition is complete, the reaction mixture is heated under reflux for 5 hours.
After cooling, the organic phase is washed carefully with water, with a 5 % strength soiution of sodium hydroxide in the presence of icé, and then again with water, and dried over sodit~n carbonate. After evaporating off the benzene, the residue, which is in the form of a-liquid, is dissolved in acetone, and a solution of hydrogen chloride in ~her is added until the pH is acid. The crystals formed are fil-tered off and washed carefully with acetone. 70 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid (m-trifluoromethyl-phenyl)-piperazinoethyl estér hydrochlorlde are thus isolated in the form of white crystals having a melting point of 199-~01c Example 3 2-Methyl-(~-lsoproPylindan-5-yl)-acetic acld chloride.
By following the procedure of Example l, but using 31 g of 2-rnethyl-(2-isopropylindan-5-yl)-acetic acid, 30 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid chloride are recovered in the form of a liquid:
Boiling point (1 mm Hg) = 150C.
Example 4 2-Methyl-(2-iso~y~lindan-5-y~l~-acetic acid (m-trifluoro-meth~lphenyl)-Piperazinoethyl ester.
A solution of 6.9 g of the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid chloride prepared in Example 3, in 2Q ml of benzene, is added dropwise to a solution of 7.5 g of (m-trifluoromethylphenyl)-piperazinoethanol and 4.5 ml of triethylamine in 100 ml of benzene.
After the addition is complete, the reaction mixture is heated under reflux for 5 hours.
After cooling, the organic phase is washed carefully with water and dried over sodium carbonate and the benzene is evaporated off in vacuo. I~e resulting residue is taken up in cold pentane. The crystals formed are fil-tered off and washed with pentane. 11 g of 2-methyl-~2-isopropylindan-5-yl~-acetic acid (m-trifluoromethylphenyl)-piperazinoethyl ester are thus isolated in the form of white crystals having a melting point of 56 - 58C.
.
llZS75~
Example ~
2-Methyl-~2-ethylindan-5-~1)-acetic acid ~m-trifluoromethyl-phenyl)-P~ipera-zinoethyl-ester hvdrochloride 21.8 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid are treated with a solution of sodium methylate, prepared from 2.3 g of sodium dissolved in 40 ml of methanol.
After evaporating off the solvent, the sodium salt of the acid is obtained in the form of a white powder.
A solution of this sodium salt and 29.3 g of ~-[~m-trifluoromethylphenyl)-piperazino]-chloroethane in 100 ml of xylene is hea-ted under reflux for 7 hours.
After cooling the reaction mixture, the organic phase is washed with water and dried over sodium carbonate.
After evaporating off the solvent, the base is isolated in the fQrm of a liquid.
This base is taken up in acetone, and a solution of hydrogen chloride in ether is added until the pH is acid.
The resulting crystals are washed carefully with acetone and dried. 36 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid (m~trifluoromethylphenyl)-piperazinoethyl ester hydro-chloride are thus recovered in the form of white crystals having a melting point of` 200 ~ 2C.
Example 6 2-Methyl-~2-isopro y ~ m-tr fluoro-methvlphenyl~-piperazinoe-thyl _ster.
By following the procedure of Example 5, but using 23.2 g OI 2-methyl-(2-isopropylindan-~-yl~-acetic acid, 11~575fj 37 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid (m--tri-fluoromethylphenyl)-piperazinoethyl ester, as the base, are recovered in the form of white crystals having a me:Lting pOi~lt of 56 - 58C.
Example 7 2-Methyl-(2-e~thylindan-5-yl)-acetic acid bromoet~yl ester.
Formula V R = ethyl Y = Br Method A:
A solution of 4.4 g of 2-me-thyl-(2 ethylindan-5-yl)-acetic acid chloride and 2.45 g of 2-bromoethanol in 50 ml of anhydrous acetone is heated under reflux for 4 hours.
After evaporating off the solven-t, the resul-ting oily residue is dissolved in ether and the ether solution is washed, in the presence of ice, with an aqueous solution of sodium bicarbonate and with water and is then dried over sodium sulphate. After filtering and evaporating off the solvent, 5.9 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid bromoethyl ester are obtained in the form of an oily residue which is used in the crude state for thef~lowingstep.
Method B:
-A solution of 12 g of 2-methyl-(2-e-thylindan-5-yl)-acetic acid chloride in 15 ml of chloroform is added, at 0~C, to a solution of 6.4 g of 2-bromoethanol and 5.5 ml of pyridine in 30 ml of chloroform.
After the addition is complete, the reaction mixture is heated under reflux for 1 hour.
` After cooling9 the reaction mix-ture is washed with 11~575~
wa-ter, with 5 % strength hydrochloric acid and then again with water. The chloroforrn phase is dried and, after evaporating off the solven~t, the oily residue is distilled in vacuo. 13.7 g of 2~methy]-(2-e-thylindan-5-yl)-acetic acid bromoethyl ester are thus recovered in the form of an oil.
Boiling poin-t ~0.2 mm Hg) = 138-lL~C.
Example 8 2-Methy]-(2-ethyl _dan-~-yl)-acetic acid m-trifluoromethyl-phcnylpi~erazinoethyl ester hydrochloride.
~ formula I R = ethyl Method A:
A solution of 5.9 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid brornoethyl ester obtained by method ~ of Example 7, in 15 ml of anhydrous acetone, is added to a solution of 4.2 g of m-trifluoromethylphenylpiperazine and
3 ml of triethylamine in 25 ml of anhydrous acetone.
The reaction mixture is s~irred for 2 hours at ambient temperature and then heated under reflux for 6 hours.
After cooling, the -triethylamine hydrobromide formed is filtered off and the filtrate is concentrated in vacuo.
The resulting residue is taken up in ether and the mixture is again filtered.
The new filtrate recovered is concentrated in vacuo.
9.8 g of oil are thus obtained.
This oil is dissolved in 50 ml of acetone~ 25 ml of water are then added and the mixture is acidified to pH 3 - Ll - llZS7S~
with concentrated hydrochloric acid.
The crystals formed are fil-tered off, washed with water and then with acetone and dried.
2.7 g of 2-methyl--(2-ethylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hydrochloride are thus recovered in the form of white crystals having a melting point of 201 - 20~C.
Method B:
A solution of 13.6 g of the 2-methyl~2-ethylindan-5-yl)-acetic acid bromoethyl ester prepared in E~ample 7 by method B, 9.6 g of m-trifluoromethylphenylpiperazine, 7 ml of triethylamine and 200 mg of sodium iodide, in 100 ml of anhydrous benzene, is heated under reflux for 10 hours.
The reaction mixture is cooled, washed carefully with water and dried over sodium sulphate and the benzene is evaporated off in vacuo.
The resulting oily residue) weighing 20 g, is taken up in 60 ml of acetone, and 3.5 ml of concentrated hydro-chloric acid, and then 40 ml of water, are added in the cold.
The crystals formed are filtered off, washed with a small amount of water and then with acetone and dried.
14.2 g of 2-methyl-~2-ethylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hydrochloride are thus recovered in the form of white crystals having a melt-ing point of 202-203C.
~ 12 ~ 75~
~ le ') -2-Methyl-(2-iso~-ropylindan-~-yl)-acetic acid bromoethyl ester.
formula V ~ = isopropyl Y = Br Me-thod A:
A solution of 32 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid chloride in 25 ml of chloroform is added, at 0C, to a solution of 16 g of 2-bromoethanol and 14 ml of pyridine in 50 ml of chloroform.
Af~ter the addition is complete, the reaction mixture is heated under reflux for 1 hour.
After cooling, the reaction mixture is washed with water, with 5 % strength hydrochloric acid and then again with water.
The chloroform phase is dried and, after evaporating off the solvent, -the oily residue~ weighing 49 g, is distil-led in vacuo. 35.2 g of 2-methyl-(2-isopropylindan-5-yl)-acetic-acid bromoethyl ester are thus recovered in the form of an oil.
Boiling point ~.5 mm Hg) = 165-175C.
Method B:
A solution of 32 g of 2-methyl-(2-isopropy]indan-5-yl)-acetic acid chloride in 25 ml of acetone is added dropwise to a solution of 16 g of 2-bromoethanol and 10.4 ml of pyridine in 125 ml of acetone.
After the addition is complete, the reaction mix-ture is heated under reflux for 1 hour 3Q minutes.
The reaction mixture is then concentrated in vacuo, the residue is taken up in ether and the resulting mixture is washed with water, with 5 % streng-th hydrochloric acld and then again with wa-ter. The ether phase is dried and the solven-t is evaporated off in vacuo.
40 g of 2-me-thyl (2-isopropylindan-5-yl)-acetic acid bromoethyl ester are thus recovered in the form of an oil w~lich is used in the crude s-tate for the follo~Jing operations Example lO
?-Methyl-(2-iso~pylindan-5-yl~-acetic acid m-trifluoro-methylphenylpipera~inoethyl ester_hydrochloride.
formula I R = isopropyl Method A: -A solution of 35.2 g of the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid bromoethyl ester prepared in Example 9 by method A, 47.8 g of m-trifluoromethylphenylpiperazine and l g of sodium iodide, in 300 ml of anhydrous toluene, is heated under reflux for 8 hours.
The reaction mixture is cooled and the m-trifluoro-methylphenylpiperazine hydrobromide is filtered off andwashed with benzene.
The organic filtrate is washed with water and then dried and concentrated in vacuo.
The resulting oily residue, weighing 61.7 g, is taken up in 250 ml of ace-tone, and 8.7 ml of concentrated hydrochloric acid, and then 150 ml of water, are addefi in the cold.
11~575~;
The resulting crystals are filtered off, washed with a small amount of water and then acetone and dried, 35.7 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hvdro-chloride are thus recovered in the form of white c~Jstals h~ving a melting point of 191~193C.
Method ~:
A solution of 40 g of -the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid bromoethyl ester prepared in Example 9 by method B, 31.5 g of m-trifluoromethylphenyl-piperazine hydrochloride and 36.5 ml of triethylamine, in 200 ml of acetone, is heated under reflux for 8 hours.
The reactlon mixture is then concentrated in vacuo, the residue is taken up in a mixture of water and ice and the resulting mixture is extracted with ether. The ether phase is washed with water, dried over sodium sulphate and then concentrated in vacuo.
The resulting residue, weighing 57 g, is taken up in 150 ml of acetone, and 10 ml o concentrated hydrochloric ?O acid, and then 100 ml of water, are added. The crystals formed are filtered ~ff, washed with a small amount of water and then acetone and dried.
27.4 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid m-trifluorome-thylphenylpiperazinoethyl es-ter hydro-chloride are thus recovered in the form of white crystals having a melting poin-t of 19~-194C.
., ~
- 1; - 11;~57S6 Method C:
A solution of 32 g of 2-oethyl-(2-isopropylindan-5-yl)-acetic acid chloride in 25 ml of chloroform is added dropwise to a solution of 16 g of 2-bromoethanol and 14 ml of pyridine in 50 ml of chloroform, whilst cooling with ice.
J After the addition ls complete, the reaction mixture is allowed to return to ambient -temperature and then heated under reflux for 1 hour.
The reaction mixture is then allowed to return to ambient temperature and 19.6 ml of triethylamine and 29.5 g of m-trifluoromethylphenylpiperazine are added.
The reaction mixture is then heated under reflux for 12 hours.
After cooling, it is diluted ~ith chloroform and the resulting mixture is washed carefully with water.
The chloroform phase is dried and the solvent is evaporated ofY in vacuo.
The resulting residue, weighing 50.7 g~ is taken up in 150 ml of acetone, and 8.5 ml of concentrated hydro-chloric acid and 100 ml of water are then added.
The resulting crystals are filtered off, washed with a small amount of water and -then with acetone and dried.
27.3 g of 2-methyl-(2-isopropylindan-5-yl)-acetic - acid m-trifluoromèthylphenylpiperazinoethyl ester hydro-chloride are thus recovered in the form of white crystals having a melting point of 193-194C.
Pharmacological results relating to the two new 112S~56 lndane aminoesters of the formula I, according to the invention, will be found below and demonstrate:
A) their analgesic action:
__________ ___________ The products being tested are administered orally (p.o.~ to batches of 12.male mice (SPF, strain OFl), weigh-ing l9-20 g. After one hour, 0.3 ml/mouse of a 0.02 %
strength solution of phenylbenzoquinone is injected intra-peritoneally and the number of pain reactions (abdominal ~ithing) is counted from the 5th to the 10th minute after the latter treatment.
The table below gives -the percen-tage inhibition of these reactions.
. . _ __,. .
mg~kg~l Example Example P-o- 2 or 5 _ _ 4 or 6 ,7 _ . _ 8 ~4 23 l268 1 775 _ _. _ ~ .. _ _ F~50 4 25 mg kg-- _ The ED50 is the medium effective dose expressed in mg/kg by oral administration.
B) their toxlcity In mice, no mortality was observed after intraperitoneal administration up to doses of:
512 mg.kg 1 for Examples 2 or 5, and 256 mg.kg for Examples 4 or 6.
The compounds (I) according to the invention therefore possess analgesic properties and have very low mammalian toxicity.
They can therefore be used in human therapy, in the form of tablets or pills, suitably sugar-coated pills, containing a dose of 100 to 200 mg, or in the form of suppositories containing a dose of 300 to S00 mg, for treating acute and chronic pain of various origins. The daily dosage for an adult can be from about 0.5 to 2 g of active ingredient.
.
The reaction mixture is s~irred for 2 hours at ambient temperature and then heated under reflux for 6 hours.
After cooling, the -triethylamine hydrobromide formed is filtered off and the filtrate is concentrated in vacuo.
The resulting residue is taken up in ether and the mixture is again filtered.
The new filtrate recovered is concentrated in vacuo.
9.8 g of oil are thus obtained.
This oil is dissolved in 50 ml of acetone~ 25 ml of water are then added and the mixture is acidified to pH 3 - Ll - llZS7S~
with concentrated hydrochloric acid.
The crystals formed are fil-tered off, washed with water and then with acetone and dried.
2.7 g of 2-methyl--(2-ethylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hydrochloride are thus recovered in the form of white crystals having a melting point of 201 - 20~C.
Method B:
A solution of 13.6 g of the 2-methyl~2-ethylindan-5-yl)-acetic acid bromoethyl ester prepared in E~ample 7 by method B, 9.6 g of m-trifluoromethylphenylpiperazine, 7 ml of triethylamine and 200 mg of sodium iodide, in 100 ml of anhydrous benzene, is heated under reflux for 10 hours.
The reaction mixture is cooled, washed carefully with water and dried over sodium sulphate and the benzene is evaporated off in vacuo.
The resulting oily residue) weighing 20 g, is taken up in 60 ml of acetone, and 3.5 ml of concentrated hydro-chloric acid, and then 40 ml of water, are added in the cold.
The crystals formed are filtered off, washed with a small amount of water and then with acetone and dried.
14.2 g of 2-methyl-~2-ethylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hydrochloride are thus recovered in the form of white crystals having a melt-ing point of 202-203C.
~ 12 ~ 75~
~ le ') -2-Methyl-(2-iso~-ropylindan-~-yl)-acetic acid bromoethyl ester.
formula V ~ = isopropyl Y = Br Me-thod A:
A solution of 32 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid chloride in 25 ml of chloroform is added, at 0C, to a solution of 16 g of 2-bromoethanol and 14 ml of pyridine in 50 ml of chloroform.
Af~ter the addition is complete, the reaction mixture is heated under reflux for 1 hour.
After cooling, the reaction mixture is washed with water, with 5 % strength hydrochloric acid and then again with water.
The chloroform phase is dried and, after evaporating off the solvent, -the oily residue~ weighing 49 g, is distil-led in vacuo. 35.2 g of 2-methyl-(2-isopropylindan-5-yl)-acetic-acid bromoethyl ester are thus recovered in the form of an oil.
Boiling point ~.5 mm Hg) = 165-175C.
Method B:
A solution of 32 g of 2-methyl-(2-isopropy]indan-5-yl)-acetic acid chloride in 25 ml of acetone is added dropwise to a solution of 16 g of 2-bromoethanol and 10.4 ml of pyridine in 125 ml of acetone.
After the addition is complete, the reaction mix-ture is heated under reflux for 1 hour 3Q minutes.
The reaction mixture is then concentrated in vacuo, the residue is taken up in ether and the resulting mixture is washed with water, with 5 % streng-th hydrochloric acld and then again with wa-ter. The ether phase is dried and the solven-t is evaporated off in vacuo.
40 g of 2-me-thyl (2-isopropylindan-5-yl)-acetic acid bromoethyl ester are thus recovered in the form of an oil w~lich is used in the crude s-tate for the follo~Jing operations Example lO
?-Methyl-(2-iso~pylindan-5-yl~-acetic acid m-trifluoro-methylphenylpipera~inoethyl ester_hydrochloride.
formula I R = isopropyl Method A: -A solution of 35.2 g of the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid bromoethyl ester prepared in Example 9 by method A, 47.8 g of m-trifluoromethylphenylpiperazine and l g of sodium iodide, in 300 ml of anhydrous toluene, is heated under reflux for 8 hours.
The reaction mixture is cooled and the m-trifluoro-methylphenylpiperazine hydrobromide is filtered off andwashed with benzene.
The organic filtrate is washed with water and then dried and concentrated in vacuo.
The resulting oily residue, weighing 61.7 g, is taken up in 250 ml of ace-tone, and 8.7 ml of concentrated hydrochloric acid, and then 150 ml of water, are addefi in the cold.
11~575~;
The resulting crystals are filtered off, washed with a small amount of water and then acetone and dried, 35.7 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid m-trifluoromethylphenylpiperazinoethyl ester hvdro-chloride are thus recovered in the form of white c~Jstals h~ving a melting point of 191~193C.
Method ~:
A solution of 40 g of -the 2-methyl-(2-isopropyl-indan-5-yl)-acetic acid bromoethyl ester prepared in Example 9 by method B, 31.5 g of m-trifluoromethylphenyl-piperazine hydrochloride and 36.5 ml of triethylamine, in 200 ml of acetone, is heated under reflux for 8 hours.
The reactlon mixture is then concentrated in vacuo, the residue is taken up in a mixture of water and ice and the resulting mixture is extracted with ether. The ether phase is washed with water, dried over sodium sulphate and then concentrated in vacuo.
The resulting residue, weighing 57 g, is taken up in 150 ml of acetone, and 10 ml o concentrated hydrochloric ?O acid, and then 100 ml of water, are added. The crystals formed are filtered ~ff, washed with a small amount of water and then acetone and dried.
27.4 g of 2-methyl-(2-isopropylindan-5-yl)-acetic acid m-trifluorome-thylphenylpiperazinoethyl es-ter hydro-chloride are thus recovered in the form of white crystals having a melting poin-t of 19~-194C.
., ~
- 1; - 11;~57S6 Method C:
A solution of 32 g of 2-oethyl-(2-isopropylindan-5-yl)-acetic acid chloride in 25 ml of chloroform is added dropwise to a solution of 16 g of 2-bromoethanol and 14 ml of pyridine in 50 ml of chloroform, whilst cooling with ice.
J After the addition ls complete, the reaction mixture is allowed to return to ambient -temperature and then heated under reflux for 1 hour.
The reaction mixture is then allowed to return to ambient temperature and 19.6 ml of triethylamine and 29.5 g of m-trifluoromethylphenylpiperazine are added.
The reaction mixture is then heated under reflux for 12 hours.
After cooling, it is diluted ~ith chloroform and the resulting mixture is washed carefully with water.
The chloroform phase is dried and the solvent is evaporated ofY in vacuo.
The resulting residue, weighing 50.7 g~ is taken up in 150 ml of acetone, and 8.5 ml of concentrated hydro-chloric acid and 100 ml of water are then added.
The resulting crystals are filtered off, washed with a small amount of water and -then with acetone and dried.
27.3 g of 2-methyl-(2-isopropylindan-5-yl)-acetic - acid m-trifluoromèthylphenylpiperazinoethyl ester hydro-chloride are thus recovered in the form of white crystals having a melting point of 193-194C.
Pharmacological results relating to the two new 112S~56 lndane aminoesters of the formula I, according to the invention, will be found below and demonstrate:
A) their analgesic action:
__________ ___________ The products being tested are administered orally (p.o.~ to batches of 12.male mice (SPF, strain OFl), weigh-ing l9-20 g. After one hour, 0.3 ml/mouse of a 0.02 %
strength solution of phenylbenzoquinone is injected intra-peritoneally and the number of pain reactions (abdominal ~ithing) is counted from the 5th to the 10th minute after the latter treatment.
The table below gives -the percen-tage inhibition of these reactions.
. . _ __,. .
mg~kg~l Example Example P-o- 2 or 5 _ _ 4 or 6 ,7 _ . _ 8 ~4 23 l268 1 775 _ _. _ ~ .. _ _ F~50 4 25 mg kg-- _ The ED50 is the medium effective dose expressed in mg/kg by oral administration.
B) their toxlcity In mice, no mortality was observed after intraperitoneal administration up to doses of:
512 mg.kg 1 for Examples 2 or 5, and 256 mg.kg for Examples 4 or 6.
The compounds (I) according to the invention therefore possess analgesic properties and have very low mammalian toxicity.
They can therefore be used in human therapy, in the form of tablets or pills, suitably sugar-coated pills, containing a dose of 100 to 200 mg, or in the form of suppositories containing a dose of 300 to S00 mg, for treating acute and chronic pain of various origins. The daily dosage for an adult can be from about 0.5 to 2 g of active ingredient.
.
Claims (16)
1. A process for the preparation of compounds of the formula (I) (I) in which R represents an ethyl or isopropyl group, their addition salts with acids, and their quaternary ammonium salts, which comprises reacting a derivative of the acid of the formula (II):
(II) which derivative is a metal salt or an acyl halide or a haloethyl ester, with a piperazine of formula (VI):
(VI) wherein Z is YCH2CH2- (Y being a halogen atom) when the derivative is a metal salt Z is HOCH2CH2 when the derivative is an acyl halide and Z is H when the derivative is a haloethyl ester, and then if desired converting the compound of formula (I) to the chosen salt.
(II) which derivative is a metal salt or an acyl halide or a haloethyl ester, with a piperazine of formula (VI):
(VI) wherein Z is YCH2CH2- (Y being a halogen atom) when the derivative is a metal salt Z is HOCH2CH2 when the derivative is an acyl halide and Z is H when the derivative is a haloethyl ester, and then if desired converting the compound of formula (I) to the chosen salt.
2. Process according to claim 1, in which the acid of formula (II) is converted to a halide (III):
(III) in which X represents a halogen atom, after which this halide (III) is reacted with an aminoalcohol of the formula:
.
(III) in which X represents a halogen atom, after which this halide (III) is reacted with an aminoalcohol of the formula:
.
3. Process according to claim 1, in which the acid of formula (II) is converted to a salt of the formula (IV):
(IV) in which M represents a metal after which this salt is reacted with a halide of the formula:
in which Y represents a halogen atom.
(IV) in which M represents a metal after which this salt is reacted with a halide of the formula:
in which Y represents a halogen atom.
4. Process according to claim 1, in which a compound of the formula:
(III) wherein R is ethyl or isopropyl is reacted with a halogeno-alcohol OHCH2CH2Y, in an organic solvent, whereby there is obtained the halogenoester of the formula:
(V) which is reacted with m-trifluoromethylphenylpiperazine of the formula:
in an organic solvent, R being an ethyl or isopropyl group and X and Y each independently being a halogen atom.
(III) wherein R is ethyl or isopropyl is reacted with a halogeno-alcohol OHCH2CH2Y, in an organic solvent, whereby there is obtained the halogenoester of the formula:
(V) which is reacted with m-trifluoromethylphenylpiperazine of the formula:
in an organic solvent, R being an ethyl or isopropyl group and X and Y each independently being a halogen atom.
5. Process according to claim 2, 3 or 4 in which the compound of formula or its addition salts with acids or its quaternary ammonium salts is prepared.
6. Process according to claim 2, 3 or 4 in which the compound of formula or its addition salts with acids or its quaternary ammonium salts is prepared.
7. Process according to claim 4, in which the solvent for the first step is acetone, chloroform, methylene chloride or an aromatic hydrocarbon.
8. Process according to claim 4, in which the first step is carried out in the presence of a base.
9. Process according to claim 8 in which pyridine or triethylamine is used as the base.
10. Process according to claim 4 or 7 in which the solvent for the second step is acetone, chloroform, methylene chloride or an aromatic hydrocarbon.
11. Process according to claim 4 in which the second step is carried out in a stoichiometric excess of m-tri-fluoromethylphenylpiperazine, or in the presence of a base containing tertiary nitrogen.
12. Process according to claim 11, in which the second step is carried out in twice the stoichiometric amount of the piperazine.
13. Process according to claim 11, in which the second step is carried out in the presence of triethylamine as tertiary nitrogen-containing base.
14. Process according to claim 1 wherein the compound prepared is a hydrochloride.
15. A compound of formula (I) as defined in claim 1 or an addition salt thereof with an acid or a quaternary ammonium salt thereof when prepared by the process claimed in claim 1 or any obvious chemical equivalent thereof.
16. A hydrochloride of the compound of formula (I) as defined in claim 1 when prepared by the process of claim 14 or any obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7821849 | 1978-07-24 | ||
| FR7821849A FR2432021A1 (en) | 1978-07-24 | 1978-07-24 | Phenyl-piperazinyl-ethyl indanyl-propionate ester(s) - useful as analgesics having low toxicity |
| FR7913532 | 1979-05-28 | ||
| FR7913532A FR2457862A2 (en) | 1979-05-28 | 1979-05-28 | Phenyl-piperazinyl-ethyl indanyl-propionate ester(s) - useful as analgesics having low toxicity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1125756A true CA1125756A (en) | 1982-06-15 |
Family
ID=26220683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA331,498A Expired CA1125756A (en) | 1978-07-24 | 1979-07-10 | Indane-acetic acid aminoesters, their preparation and their use in therapy |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4271161A (en) |
| EP (2) | EP0034838A3 (en) |
| AR (2) | AR220210A1 (en) |
| AU (1) | AU516742B2 (en) |
| CA (1) | CA1125756A (en) |
| ES (2) | ES482656A0 (en) |
| GB (3) | GB2038830A (en) |
| GR (1) | GR65999B (en) |
| PH (1) | PH14387A (en) |
| PT (1) | PT69941A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4339580A (en) * | 1979-06-26 | 1982-07-13 | Mitsubishi Chemical Industries, Limited | Piperazinylalkoxyindanes and acid addition salts thereof |
| DE3377415D1 (en) * | 1983-11-09 | 1988-08-25 | Juste Sa | Novel phenylpiperazine derivatives, process for preparing them and therapeutic compositions containing them |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2258840A1 (en) * | 1974-01-29 | 1975-08-22 | Synthelabo | (4-Phenylpiperazino) alkyl esters - with analgesic activity for human and veterinary use |
| GB1437868A (en) * | 1973-05-09 | 1976-06-03 | Synthelabo | Arylpiperazinoalkyl esters |
| AR206619A1 (en) | 1974-02-07 | 1976-08-06 | Hexachimie | PROCEDURE FOR PEPARING 5-INDANILACETIC ACIDS |
| FR2341313A1 (en) * | 1976-02-23 | 1977-09-16 | Roussel Uclaf | NEW SUBSTITUTED QUINOLEINES, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT |
| SE7712447L (en) * | 1977-01-21 | 1978-07-22 | Roussel Uclaf | WAY TO PRODUCE NEW BENZOPHENONE DERIVATIVES |
-
1979
- 1979-06-09 GR GR59316A patent/GR65999B/el unknown
- 1979-07-03 GB GB8002206A patent/GB2038830A/en not_active Withdrawn
- 1979-07-03 GB GB08210290A patent/GB2103599B/en not_active Expired
- 1979-07-03 GB GB7923195A patent/GB2027019B/en not_active Expired
- 1979-07-06 AR AR277223A patent/AR220210A1/en active
- 1979-07-09 US US06/055,907 patent/US4271161A/en not_active Expired - Lifetime
- 1979-07-10 CA CA331,498A patent/CA1125756A/en not_active Expired
- 1979-07-13 EP EP81103269A patent/EP0034838A3/en not_active Withdrawn
- 1979-07-13 EP EP79400500A patent/EP0008256A3/en not_active Withdrawn
- 1979-07-18 AU AU49019/79A patent/AU516742B2/en not_active Ceased
- 1979-07-18 PT PT69941A patent/PT69941A/en unknown
- 1979-07-19 ES ES482656A patent/ES482656A0/en active Granted
- 1979-07-23 PH PH22804A patent/PH14387A/en unknown
-
1980
- 1980-06-02 ES ES492085A patent/ES492085A0/en active Granted
- 1980-08-26 AR AR282297A patent/AR220500A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| EP0008256A2 (en) | 1980-02-20 |
| PT69941A (en) | 1979-08-01 |
| GB2103599A (en) | 1983-02-23 |
| GB2103599B (en) | 1983-06-08 |
| EP0034838A2 (en) | 1981-09-02 |
| AU4901979A (en) | 1980-01-31 |
| GB2027019A (en) | 1980-02-13 |
| GR65999B (en) | 1981-01-13 |
| ES8101063A1 (en) | 1980-12-01 |
| AR220500A1 (en) | 1980-10-31 |
| ES8104254A1 (en) | 1981-04-16 |
| ES492085A0 (en) | 1981-04-16 |
| US4271161A (en) | 1981-06-02 |
| EP0008256A3 (en) | 1980-12-10 |
| AR220210A1 (en) | 1980-10-15 |
| EP0034838A3 (en) | 1981-10-07 |
| GB2038830A (en) | 1980-07-30 |
| ES482656A0 (en) | 1980-12-01 |
| PH14387A (en) | 1981-06-24 |
| GB2027019B (en) | 1983-01-06 |
| AU516742B2 (en) | 1981-06-18 |
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